A heterocyclic compound and its application

Abstract

A heterocyclic compound having the structure shown in formula (I) is provided. Experimental results show that by selecting specific modifying groups, the heterocyclic compound, as a TRβ agonist, has a significantly improved activity compared to the prior art and has a higher TRβ selectivity, can be used for treating and / or preventing diseases caused by thyroid hormone regulation, and has lower side effects.

Description

[0001] This application is based on an application with a CN application number of 202110557323.0 and a filing date of May 21, 2021, and claims its priority. The disclosure of this CN application is hereby incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to the technical field of medicinal chemistry, and particularly relates to a heterocyclic compound and its application. Background Art

[0003] Thyroid hormone (TH) plays a key role in normal growth and development and maintaining metabolic balance (Paul M Yen, Physiological Reviews, 81(3): 1097 - 1126 (2001)). TH can promote lipid hydrolysis, increase the availability of fatty acids, thereby providing energy for the body, and finally leading to a reduction in lipids and a decrease in body weight. Studies have shown that the TH levels in obese patients vary greatly compared with those in normal people. TH mainly has two forms: 3,5,3',5'-tetraiodo-L-thyronine (T4) and 3,5,3'-triiodo-L-thyronine (T3). Although T4 is the main form secreted by the thyroid gland, T3 is the more physiologically active form. T4 is converted into T3 by tissue-specific deiodinases, which are present in all tissues but mainly in the liver and kidneys. Relevant studies have shown that T3 or T3 analogs can effectively treat obesity, especially when combined with a low-calorie diet, the weight loss effect is more obvious. Therefore, controlling the level of TH can effectively regulate energy balance. Clinically, it has been observed that hypothyroidism can reduce cholesterol excretion, decrease the number of low-density lipoprotein-cholesterol (LDL-C) receptors on the liver surface, thereby reducing the breakdown of LDL-C. Therefore, patients often show elevated total cholesterol and LDL-C levels, leading to metabolic syndromes such as hyperlipidemia, atherosclerosis, insulin resistance, and non-alcoholic fatty liver disease (NAFLD).

[0004] From a pathophysiological perspective, tachycardia, arrhythmia, heart failure, as well as fatigue, shortness of breath, skeletal muscle reduction, osteoporosis, etc. have been observed in hyperthyroidism (Physiology Review, 81: 1097 (2001)). Conversely, beneficial effects on the treatment of metabolic diseases such as reduced cholesterol in the blood and increased basal metabolism have also been observed. On the contrary, a decrease in heart rate, an increase in blood cholesterol, and an increase in body weight have been observed in hypothyroidism caused by pituitary disorders and congenital dysfunctions, etc. This is also the reason why the therapeutic use of naturally occurring thyroid hormones is limited due to their cardiotoxicity.

[0005] From a molecular biology perspective, the biological activity of TH is mediated by nuclear receptors - thyroid hormone receptors (TRs) (M.A. Lazar, Endocrine Reviews, Volume 14: pp. 348 - 399 (1993)). TRs form heterodimers with retinoic acid receptors that act as ligand - induced transcription factors. TRs have a ligand - binding domain, a DNA - binding domain, and an amino - terminal domain, and regulate gene expression through interactions with corresponding elements of NDA and with various nuclear co - activators and co - repressors. TRs are encoded by different genes α and β located on human chromosomes 17 and 3 respectively, and different protein subtypes are generated by selective splicing of primary transcripts, with each gene producing two subtypes: α1, α2, β1, and β2. TRα1, TRβ1, and TRβ2 can bind to T3, while TRα2 does not bind to TH. Studies have shown that thyroid hormone receptor subtypes can differ in their contributions to specific physiological responses. TRβ1 is present in most tissues, especially the liver. The distribution of TRα1 is also relatively widespread, and TH has similar activity when binding to TRα1 and TRβ1, but its distribution range is smaller than that of TRβ1. Studies have shown that most of the effects of TH on the heart, especially heart rhythm and heart rate, are mainly achieved through the TRα1 subtype.

[0006] Since TH mainly maintains metabolic balance by regulating gene expression on target organs (liver) through receptors, including maintaining lipid balance in the liver and adipose tissue. Therefore, while avoiding the above - mentioned harmful events, particularly exerting the beneficial aspects of TH and its analogs such as cholesterol reduction or increased basal metabolism, and having a special accumulation in the liver has clinical significance, which will open up new treatment avenues for patients with the following diseases: metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other diseases such as hepatic steatosis and non - alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, etc. Therefore, it is of great significance to provide thyroid hormone β - receptor agonists for the treatment and / or prevention of diseases regulated by thyroid hormones.

[0007] The applicant's prior Chinese patent application CN112300133A has disclosed a heterocyclic compound structure with agonist activity for thyroid hormone receptor β. On this basis, the applicant has further optimized and modified this series of TRβ agonists in order to obtain more pharmaceutically acceptable compounds with higher selectivity for TRβ and stronger agonist activity. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a heterocyclic compound. Compared with the prior art, the heterocyclic compound provided by the present invention has more excellent TRβ agonist activity and TRβ selectivity.

[0009] To achieve the above-mentioned invention object, the present invention provides the following technical solutions:

[0010] A heterocyclic compound having the structure shown in formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:

[0011]

[0012] Wherein:

[0013] X is selected from N or CH;

[0014] R1 and R2 are independently selected from F, Cl, Br, I or substituted or unsubstituted C1-C6 alkyl;

[0015] Preferably, R1 and R2 are independently selected from Cl, Br or substituted or unsubstituted C1-C3 alkyl;

[0016] Preferably, R1 and R2 are independently selected from Cl or Br;

[0017] Preferably, R1 and R2 are the same group;

[0018] R3 is selected from C1-C6 alkyl or C3-C8 cycloalkyl, and the C1-C6 alkyl or C3-C8 cycloalkyl is unsubstituted or independently substituted by one or more of the following groups: D, F, Cl, Br or substituted or unsubstituted C1-C3 alkyl; wherein, when R1 and R2 are both Cl and X is CH, R3 is not methyl;

[0019] Preferably, R3 is selected from C1-C4 alkyl or C3-C6 cycloalkyl; preferably, the C1-C4 alkyl or C3-C6 cycloalkyl is unsubstituted or independently substituted by one or more of the following substituents: F, Cl or Br;

[0020] Preferably, R3 is selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl, and preferably, the substituents of methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl are independently selected from one or more of the following groups: F, Cl or Br.

[0021] In some embodiments, both R1 and R2 are Cl.

[0022] In some embodiments, both R1 and R2 are Br.

[0023] In some embodiments, X is CH;

[0024] Both R1 and R2 are Br;

[0025] R3 is selected from C1-C6 alkyl or C3-C8 cycloalkyl, and the C1-C6 alkyl or C3-C8 cycloalkyl is unsubstituted or independently substituted by one or more of the following groups: D, F, Cl, Br, or substituted or unsubstituted C1-C3 alkyl;

[0026] Preferably, R3 is selected from C1-C6 alkyl, and the C1-C6 alkyl is unsubstituted or independently substituted by one or more of the following groups: D, F, Cl, Br, or substituted or unsubstituted C1-C3 alkyl;

[0027] Preferably, R3 is selected from C1-C4 alkyl;

[0028] Preferably, R3 is selected from methyl, ethyl, propyl, and isopropyl.

[0029] In some embodiments, X is CH;

[0030] Both R1 and R2 are Cl;

[0031] R3 is selected from C2-C6 alkyl or C3-C8 cycloalkyl, and the C2-C6 alkyl or C3-C8 cycloalkyl is unsubstituted or independently substituted by one or more of the following groups: D, F, Cl, Br, or substituted or unsubstituted C1-C3 alkyl;

[0032] Preferably, R3 is selected from C2-C4 alkyl or C3-C6 cycloalkyl, and the C2-C4 alkyl or C3-C6 cycloalkyl is unsubstituted or independently substituted by one or more of the following substituents: F, Cl, or Br;

[0033] Preferably, R3 is selected from ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl is unsubstituted or independently substituted by one or more of the following substituents: F, Cl, or Br;

[0034] Preferably, R3 is selected from ethyl, isopropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and cyclobutyl;

[0035] Preferably, R3 is selected from ethyl, isopropyl, and cyclobutyl.

[0036] In some embodiments, X is N;

[0037] R1 and R2 are independently selected from F, Cl, Br, I, or substituted or unsubstituted C1-C6 alkyl;

[0038] R3 is selected from C1-C6 alkyl or C3-C8 cycloalkyl, and the C1-C6 alkyl or C3-C8 cycloalkyl is unsubstituted or independently substituted by one or more of the following groups: D, F, Cl, Br, or substituted or unsubstituted C1-C3 alkyl.

[0039] In some embodiments, X is N;

[0040] Both R1 and R2 are Cl;

[0041] R3 is selected from C1-C6 alkyl or C3-C8 cycloalkyl, and the C1-C6 alkyl or C3-C8 cycloalkyl is unsubstituted or independently substituted by one or more of the following groups: D, F, Cl, Br, or substituted or unsubstituted C1-C3 alkyl;

[0042] Preferably, R3 is selected from C1-C4 alkyl or C3-C6 cycloalkyl, and the C1-C4 alkyl or C3-C6 cycloalkyl is unsubstituted or independently substituted by one or more of the following substituents: F, Cl, or Br;

[0043] Preferably, R3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl is unsubstituted or independently substituted by one or more of the following substituents: F, Cl, or Br;

[0044] Preferably, R3 is selected from methyl, isopropyl, and cyclopropyl.

[0045] In some embodiments, X is selected from N or CH;

[0046] Both R1 and R2 are Cl;

[0047] R3 is selected from C2-C6 alkyl or C3-C8 cycloalkyl, and the C2-C6 alkyl or C3-C8 cycloalkyl is unsubstituted or independently substituted by one or more of the following groups: D, F, Cl, Br, or substituted or unsubstituted C1-C3 alkyl;

[0048] Preferably, R3 is selected from C2-C4 alkyl or C3-C6 cycloalkyl, and the C2-C4 alkyl or C3-C6 cycloalkyl is unsubstituted or independently substituted by one or more of the following substituents: F, Cl, or Br;

[0049] Preferably, R3 is selected from ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl, and the ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl is unsubstituted or independently substituted by one or more of the following substituents: F, Cl, or Br;

[0050] Preferably, R3 is selected from ethyl, isopropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclopropyl, or cyclobutyl.

[0051] In some embodiments, the heterocyclic compound is selected from the following specific compounds:

[0052]

[0053]

[0054] Preparation method:

[0055] The present invention also provides a method for preparing the said compound. The preparation of the compound of general formula (I) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way. The compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or by comprehensively using the synthetic methods known in the art and the methods of the present invention. The products obtained from each step of the reaction are obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (such as provided by Scifinder) or purchased.

[0056] The compound of general formula (I) of the present invention can be synthesized according to the following routes: 1) After the starting material A is alkalized in a low-temperature organic solvent, it undergoes a condensation reaction with the alkyl halide of R3 (Compound 1) at room temperature to obtain Intermediate A1; 2) Intermediate A1 undergoes a substitution reaction with p-aminophenol (Compound 2) containing R1 and R2 substituents to obtain Intermediate A2; 3) Intermediate A2 is diazotized and then undergoes a substitution reaction with N-cyanoacetylurethane (Compound 3) to generate Intermediate A3; 4) Intermediate A3 undergoes intramolecular defatting condensation to obtain the target compound of formula I.

[0057]

[0058] Among them, the definitions of R1, R2, and R3 are as described above.

[0059] Drug composition:

[0060] Another object of the present invention is also to provide a pharmaceutical composition. The said pharmaceutical composition includes a therapeutically and / or prophylactically effective amount of the heterocyclic compound of formula (I) as described above or a pharmaceutically acceptable salt or stereoisomer thereof, and optionally a pharmaceutically acceptable pharmaceutical carrier and / or excipient and / or diluent.

[0061] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known or will be apparent to those skilled in the art in light of the disclosure of the present invention. As described in REMINGTON’S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995), methods for preparing such pharmaceutical compositions include incorporating suitable pharmaceutical excipients, carriers, diluents, and the like.

[0062] Medical use:

[0063] In another aspect, the present invention also provides the use of the compound or its pharmaceutically acceptable salt / stereoisomer, or the pharmaceutical composition, in the preparation of an agonist that stimulates thyroid hormones.

[0064] In another aspect, the present invention also provides the use of the compound or its pharmaceutically acceptable salt / stereoisomer, or the pharmaceutical composition, in the preparation of a medicament for treating and / or preventing thyroid hormone-related diseases.

[0065] In another aspect, the present invention also provides the use of the compound or its pharmaceutically acceptable salt / stereoisomer, or the pharmaceutical composition, in the treatment and / or prevention of thyroid hormone-related diseases.

[0066] Another object of the present invention is to provide a method for treating and / or preventing thyroid hormone-related diseases, which comprises administering to an individual in need a therapeutically and / or prophylactically effective amount of: the compound or its pharmaceutically acceptable salt / stereoisomer, or the pharmaceutical composition.

[0067] In another aspect, the present invention also provides the use of the compound or its pharmaceutically acceptable salt / stereoisomer, or the pharmaceutical composition, in the preparation of a thyroid hormone receptor agonist, particularly a thyroid hormone β receptor agonist (such as a thyroid hormone β1 receptor agonist).

[0068] In another aspect, the present invention also provides the use of the compound or its pharmaceutically acceptable salt / stereoisomer, or the pharmaceutical composition, in the preparation of a medicament for treating and / or preventing thyroid hormone-related diseases.

[0069] In another aspect, the present invention also provides the compound or its pharmaceutically acceptable salt / stereoisomer, or the pharmaceutical composition, for use in the treatment and / or prevention of thyroid hormone-related diseases.

[0070] In another aspect, the present invention also provides a method for treating and / or preventing thyroid hormone-related diseases, comprising administering to an individual in need thereof a therapeutically and / or prophylactically effective amount of the described compound or its pharmaceutically acceptable salt / stereoisomer, or the described pharmaceutical composition.

[0071] In some embodiments, the thyroid hormone-related diseases are metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, hepatic steatosis, non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular diseases, hypothyroidism or thyroid cancer.

[0072] In the present invention, "treatment" generally refers to obtaining the desired pharmacological and / or physiological effects, covering any treatment of the patient's disease, including: (a) inhibiting the symptoms of the disease, i.e., preventing its development; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0073] In the present invention, "individual" refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cows), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

[0074] In the present invention, "effective amount" refers to the amount that is effective in achieving the desired therapeutic or prophylactic effect at the required dose and time. The "therapeutically effective amount" of the substance / molecule of the present invention may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule to elicit the desired response in the individual. The therapeutically effective amount also encompasses the amount where the therapeutic beneficial effects of the substance / molecule outweigh any toxic or harmful consequences. "Prophylactically effective amount" refers to the amount that is effective in achieving the desired prophylactic effect at the required dose and time. Usually but not necessarily, since the prophylactic dose is used in the subject before the onset of the disease or in the early stage of the disease, the prophylactically effective amount will be lower than the therapeutically effective amount. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; shrink the tumor volume; inhibit (i.e., slow down to a certain extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms related to cancer to a certain extent.

[0075] Terms and Definitions:

[0076] It should be understood that the terms used herein are for the purpose of describing specific embodiments and are not intended to be limiting. In addition, although any methods, devices, and materials similar or equivalent to those described herein can be used to practice or test the present invention, the preferred methods, devices, and materials are now described.

[0077] As used herein, examples of the term "pharmaceutically acceptable salts of the compounds of formula (I)" are organic acid addition salts formed by organic acids that form pharmaceutically acceptable anions, including but not limited to formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, ascorbates, α-ketoglutarates, α-glycerophosphates, alkylsulfonates or arylsulfonates; preferably, the alkylsulfonate is methylsulfonate or ethylsulfonate; the arylsulfonate is benzenesulfonate or p-toluenesulfonate. Suitable inorganic salts can also be formed, including but not limited to hydrochlorides, hydrobromides, hydroiodides, nitrates, bicarbonates and carbonates, sulfates or phosphates, etc. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.

[0078] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. Specifically, the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C 1-6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl independently disclosed, or "C 2-6 alkyl" independently disclosed, or "C 1-4 alkyl" independently disclosed, or "C 1-3 alkyl" independently disclosed.

[0079] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group. For example, C1 to C6 alkyl, specifically such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tert-butyl), etc.

[0080] The term "alkenyl" refers to a hydrocarbon chain including a straight-chain or branched-chain configuration and having one or more carbon-carbon double bonds that can be present at any stable point along the chain. For example, "C 2-6 alkenyl" includes C2, C3, C4, C5 and C6 alkenyl. Examples of alkenyl include but are not limited to vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.

[0081] The term "alkynyl" refers to a hydrocarbon group including a straight-chain or branched-chain configuration and having one or more carbon-carbon triple bonds that can be present at any stable point along the chain. For example, "C 2-6 alkynyl" includes C2, C3, C4, C5 and C6 alkynyl. Examples of alkynyl include but are not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0082] The alkyl and cycloalkyl groups can be substituted or unsubstituted. In the case of substitution, there are generally 1 to 4 substituents, preferably 2 - 3 substituents. The substituents can include, for example: carbon-containing groups such as alkyl, aryl, aralkyl (e.g., substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g., trifluoromethyl); oxygen-containing groups such as alcohols (hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl), ethers (e.g., alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g., formaldehyde), ketones (e.g., alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl), acids (e.g., carboxylic acid, carboxyalkyl), acid derivatives such as esters (e.g., alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxyalkyl), amides (e.g., aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (e.g., alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyl-oxy, mono- or di-alkylaminocarbonylamino or arylaminocarbonylamino); nitrogen-containing groups such as amines (amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides, nitriles (e.g., cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (e.g., alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl).

[0083] As used herein, the term "substituted" means that any one or more hydrogens on a specified atom or group are selectively replaced by a specified group, provided that the normal valence of the specified atom is not exceeded.

[0084] The term "cycloalkyl" refers to a cyclized alkyl group including a monocyclic, bicyclic or polycyclic system. C 3-7 Cycloalkyl refers to including C3, C4, C5, C6 and C7 cycloalkyls, such as C 3-6 cycloalkyls. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0085] The term "aryl" refers to an aromatic hydrocarbon group having a monocyclic or fused ring, such as a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 ring-forming carbon atoms, such as phenyl and naphthyl.

[0086] The terms "heterocyclic", "heterocycloalkyl", "heterocyclic" or "heterocyclic group" are used interchangeably and include 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, wherein at least one ring has at least one heteroatom (O, S or N), and the heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms selected from O, S and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atoms may be optionally quaternized. The fused rings that complete the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or fully unsaturated. The heterocyclic group may be attached at any available nitrogen or carbon atom.

[0087] Beneficial effects

[0088] Compared with the prior art, the present invention provides a heterocyclic compound having the structure shown in formula (I): By selecting specific modifying groups, the experimental results show that the heterocyclic compound provided by the present invention has better activity and / or selectivity as a thyroid hormone β receptor agonist compared with the prior art, and can be used for treating and / or preventing diseases caused by thyroid hormone regulation. Detailed Description of the Invention

[0089] The present invention provides a heterocyclic compound and its application. Those skilled in the art can draw on the content of this article and appropriately modify the structure and groups to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they all belong to the scope of protection of the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate alterations and combinations to the methods and applications herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0090] In order to further illustrate the present invention, the following is a detailed description of a heterocyclic compound and its application provided by the present invention in combination with embodiments.

[0091] Example 1

[0092] Preparation of 2-(3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0093]

[0094] Step 1: Preparation of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine

[0095] Dissolve 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (307 mg, 2 mmol) in tetrahydrofuran (5 ml), protect with nitrogen, cool down to 0 - 5 °C, and then add sodium hydride (144 mg, 6 mmol) portionwise. After the addition is complete, keep the reaction at a constant temperature for 30 minutes, then add methyl iodide (570 mg, 4 mmol), raise the temperature to room temperature, and continue stirring the reaction for 2 hours. After the reaction is complete, slowly add water (20 ml), then extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, filter, distill under reduced pressure to obtain a residue, and finally add petroleum ether and stir to crystallize, filter, and dry the filter cake to obtain the target 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (310 mg, 92.5% yield), LC-MS (m / z) 168.6 (M + 1).

[0096] Step 2: Preparation of 3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline

[0097] Dissolve 2,6-dibromo-4-aminophenol (320 mg, 1.2 mmol) and 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (168 mg, 1 mmol) in N,N-dimethylformamide (10 ml), and then add cesium carbonate (815 mg, 2.5 mmol). After the addition is complete, displace and protect the reaction system with nitrogen, heat and stir to raise the temperature to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system and stir to filter, add saturated brine to the filtrate for extraction, dry the organic phase, filter, distill under reduced pressure to obtain a residue, and finally separate by column chromatography (ethyl acetate / petroleum ether = 1 / 3). Obtain the target 3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (63 mg, 15.8% yield), LC-MS (m / z) 399.2 (M + 1).

[0098] Step 3: Preparation of ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate

[0099] Dissolve 3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (63 mg, 0.16 mmol) in a solution of hydrochloric acid (2 ml) and water (2 ml). Cool the solution to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (14 mg, 0.19 mmol). Keep the reaction at this temperature for 30 minutes to obtain the reaction mother liquor. Dissolve N-cyanoacetylurethane (27 mg, 0.17 mmol) in a solution of pyridine (2 ml) and water (2 ml). Cool the solution to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor into the system. After the addition is complete, the solution turns light brown and a solid precipitates. Continue to keep the reaction at this temperature for 1 hour. Add a small amount of water to the reaction solution, stir, filter by suction, and wash the filter residue with water. Dry the solid to obtain the target ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (74 mg, 82.8% yield), LC-MS (m / z) 566.2 (M+1).

[0100] Step 4: Preparation of 2-(3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0101] At room temperature, dissolve ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (74 mg, 0.13 mmol) in 5 ml of acetic acid, then add sodium acetate (54 mg, 0.65 mmol). Heat the mixture to 100 °C and stir the reaction for 5 hours, then stop heating. Cool to room temperature, add ice water, and a solid precipitates. Filter the solid, then dissolve it in EA, dry and concentrate to obtain a crude red solid. Separate by column chromatography (methanol / dichloromethane = 1 / 20) to obtain the target compound 2-(3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (51 mg, 74.7% yield), LC-MS (m / z) 520.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.95 (s, 3H), 7.62 (d, J = 3.5 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1H), 3.86 (s, 4H).

[0102] Example 2 Preparation of 2-(3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0103]

[0104] Step 1: Preparation of 4-chloro-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine

[0105] Dissolve 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (922 mg, 6 mmol) in N,N-dimethylformamide (10 ml), protect with nitrogen, add potassium hydroxide (672 mg, 12 mmol) at room temperature, cool in an ice-water bath, stir vigorously, then add bromoethane (785 mg, 7.2 mmol), and continue stirring at room temperature for 1 hour. After the reaction is complete, add water (20 ml), then extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, filter, distill under reduced pressure to obtain a residue, and finally separate by column chromatography (ethyl acetate / petroleum ether = 1 / 5). The target 4-chloro-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine (955 mg, 87.7% yield) is obtained, LC-MS (m / z) 182.6 (M+1).

[0106] Step 2: Preparation of 3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline

[0107] Dissolve 2,6-dichloro-4-aminophenol (214 mg, 1.2 mmol) and 4-chloro-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine (182 mg, 1 mmol) in N,N-dimethylformamide (10 ml), and then add cesium carbonate (815 mg, 2.5 mmol). After adding the materials, replace the reaction system with nitrogen for protection, heat and stir to raise the temperature to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system and stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, distill under reduced pressure to obtain a residue, and finally separate by column chromatography (ethyl acetate / petroleum ether = 1 / 3). The target 3,5-dichloro-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (225 mg, 69.5% yield) is obtained, LC-MS (m / z) 324.2 (M+1).

[0108] Step 3: Preparation of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate

[0109] Dissolve 3,5-dichloro-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (225 mg, 0.7 mmol) in a solution of hydrochloric acid (3 ml) and water (3 ml), cool down to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (58 mg, 0.85 mmol). Keep the temperature and react for 30 minutes to obtain the reaction mother liquor. Dissolve N-cyanoacetylurethane (116 mg, 0.74 mmol) in a solution of pyridine (3 ml) and water (3 ml), cool down to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor into the system. After the addition is complete, the solution turns red and a solid precipitates. Continue to keep the temperature and react for 1 hour. Add a small amount of water to the reaction solution, stir, filter by suction, and wash the filter residue with water. Dry the solid to obtain the target ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (248 mg, 72.7% yield), LC-MS (m / z) 491.3 (M + 1).

[0110] Step 4: Preparation of 2-(3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0111] At room temperature, dissolve ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (248 mg, 0.5 mmol) in 5 ml of acetic acid, then add sodium acetate (205 mg, 2.5 mmol), heat up to 100 °C and stir to react for 5 hours, and stop heating. Cool to room temperature, add ice water, a solid precipitates, filter, then dissolve with EA, dry and concentrate to obtain a crude red solid. Separate by column chromatography (methanol / dichloromethane = 1 / 20) to obtain the target compound 2-(3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (152 mg, 68.5% yield), LC-MS (m / z) 445.2 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.81 (s, 2H), 7.69 (d, J = 3.5 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H).

[0112] Preparation of Example 3: 2-(3,5-Dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0113]

[0114] Step 1: Preparation of 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

[0115] Dissolve 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (922 mg, 6 mmol) in N,N-dimethylformamide (10 ml). Under nitrogen protection, add potassium hydroxide (672 mg, 12 mmol) at room temperature, stir vigorously, then add isopropyl iodide (1.23 g, 7.2 mmol), and continue to stir at room temperature for 8 hours. After the reaction is completed, add water (20 ml) dropwise, then extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, filter, distill under reduced pressure to obtain a residue, and finally separate by column chromatography (ethyl acetate / petroleum ether = 1 / 6). The target product 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (905 mg, 77.1% yield) is obtained, LC-MS (m / z) 196.6 (M+1).

[0116] Step 2: Preparation of 3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline

[0117] Dissolve 2,6-dichloro-4-aminophenol (214 mg, 1.2 mmol) and 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (196 mg, 1 mmol) in N,N-dimethylformamide (10 ml), and then add cesium carbonate (815 mg, 2.5 mmol). After adding the materials, replace the reaction system with nitrogen for protection, heat and stir to raise the temperature to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system and stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, distill under reduced pressure to obtain a residue, and finally separate by column chromatography (ethyl acetate / petroleum ether = 1 / 3). The target product 3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (223 mg, 66.0% yield) is obtained, LC-MS (m / z) 338.2 (M+1).

[0118] Step 3: Preparation of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate

[0119] 3,5-Dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (222 mg, 0.65 mmol) was dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml). The temperature was cooled to 0 - 5 °C, and then an aqueous solution of sodium nitrite (54 mg, 0.78 mmol) was added dropwise. The reaction was maintained for 30 minutes to obtain a reaction mother liquor. N-Cyanoacetylurethane (106 mg, 0.68 mmol) was dissolved in a solution of pyridine (3 ml) and water (3 ml). The temperature was cooled to 0 - 5 °C, and then the diazonium salt reaction mother liquor prepared above was added dropwise to the system. After the addition was complete, the solution turned red and a solid precipitated. The reaction was continued while maintaining the temperature for 1 hour. A small amount of water was added to the reaction solution, stirred, filtered, and the filter cake was washed with water. The solid was dried to obtain the target ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (239 mg, 71.8% yield), LC-MS (m / z) 505.3 (M+1).

[0120] Step 4: Preparation of 2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0121] At room temperature, ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (239 mg, 0.47 mmol) was dissolved in 5 ml of acetic acid, and then sodium acetate (189 mg, 2.3 mmol) was added. The temperature was raised to 100 °C and stirred for 5 hours, then the heating was stopped. After cooling to room temperature, ice water was added, and a solid precipitated. It was filtered, then dissolved in EA, dried and concentrated to obtain a crude red solid. Column chromatography separation (methanol / dichloromethane = 1 / 20) gave the target compound 2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (101 mg, 46.6% yield). LC-MS (m / z) 459.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.87 - 7.71 (m, 3H), 6.76 (d, J = 3.6 Hz, 1H), 5.05 (p, J = 6.8 Hz, 1H), 1.51 (d, J = 6.8 Hz, 6H).

[0122] Example 4 Preparation of 2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0123]

[0124] Step 1: Preparation of 3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline

[0125] Dissolve 2,6-dibromo-4-aminophenol (615 mg, 2.4 mmol) and 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (392 mg, 2 mmol) in N,N-dimethylformamide (15 ml), and then add cesium carbonate (1.6 g, 5 mmol). After the addition is complete, replace the reaction system with nitrogen for protection, heat and stir to raise the temperature to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, distill under reduced pressure to obtain a residue, and finally separate by column chromatography (ethyl acetate / petroleum ether = 1 / 2). The target 3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (123 mg, 14.5% yield) is obtained, LC-MS (m / z) 427.1 (M+1).

[0126] Step 2: Preparation of ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate

[0127] Dissolve 3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (123 mg, 0.29 mmol) in a solution of hydrochloric acid (3 ml) and water (3 ml). Cool the temperature to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (24 mg, 0.35 mmol). Keep the reaction at a constant temperature for 30 minutes to obtain the reaction mother liquor. Dissolve N-cyanoacetylurethane (48 mg, 0.31 mmol) in a solution of pyridine (3 ml) and water (3 ml). Cool the temperature to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor into the system. After the addition is complete, the solution turns brown and a solid precipitates. Continue to keep the reaction at a constant temperature for 1 hour. Add a small amount of water to the reaction solution, stir, filter by suction, and wash the filter residue with water. Dry the solid to obtain the target ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (126 mg, 86.5% yield), LC-MS (m / z) 505.3 (M + 1).

[0128] Step 3: Preparation of 2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0129] At room temperature, dissolve ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (126 mg, 0.25 mmol) in 5 ml of acetic acid, and then add sodium acetate (103 mg, 1.25 mmol). Heat the temperature to 100 °C and stir the reaction for 4 hours, then stop heating. Cool to room temperature, add ice water, and a solid precipitates. Filter, then dissolve in EA, dry and concentrate to obtain a crude red solid. Separate by column chromatography (methanol / dichloromethane = 1 / 20) to obtain the target compound 2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (53 mg, 46.3% yield). LC-MS (m / z) 459.3 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.94 (d, J = 0.8 Hz, 2H), 7.79 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 5.04 (q, J = 6.7 Hz, 1H), 1.51 (d, J = 6.7 Hz, 8H).

[0130] Preparation of Example 5: 2-(3,5-Dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0131]

[0132] Step 1: Preparation of 4-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine

[0133] Dissolve 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (922 mg, 6 mmol) in N,N-dimethylformamide (10 ml). Under nitrogen protection, add potassium hydroxide (672 mg, 12 mmol) at room temperature, stir vigorously, then add cyclobutyl bromide (972 mg, 7.2 mmol), and continue to stir at room temperature for 48 hours. The reaction is incomplete. Add water (20 ml), then extract with ethyl acetate. Wash the organic phase with saturated brine, dry the organic phase, filter, and distill under reduced pressure to obtain a residue. Finally, separate by column chromatography (ethyl acetate / petroleum ether = 1 / 6). Obtain the target 4-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine (211 mg, 16.9% yield), LC-MS (m / z) 208.7 (M+1).

[0134] Step 2: Preparation of 3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline

[0135] Dissolve 2,6-dichloro-4-aminophenol (215 mg, 1.2 mmol) and 4-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine (211 mg, 1 mmol) in N,N-dimethylformamide (10 ml), and then add cesium carbonate (815 mg, 2.5 mmol). After adding the materials, replace the reaction system with nitrogen for protection, heat and stir to raise the temperature to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system and stir and filter. Add saturated brine to the filtrate, extract, dry the organic phase, filter, and distill under reduced pressure to obtain a residue. Finally, separate by column chromatography (ethyl acetate / petroleum ether = 1 / 3). Obtain the target 3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (219 mg, 61.7% yield), LC-MS (m / z) 350.2 (M+1).

[0136] Step 3: Preparation of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate

[0137] Dissolve 3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (219 mg, 0.63 mmol) in a solution of hydrochloric acid (3 ml) and water (3 ml), cool down to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (53 mg, 0.76 mmol). Keep the reaction at a constant temperature for 30 minutes to obtain the reaction mother liquor. Dissolve N-cyanoacetylurethane (103 mg, 0.66 mmol) in a solution of pyridine (3 ml) and water (3 ml), cool down to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor into the system. After the addition is complete, the solution turns orange-red and a solid precipitates. Continue to keep the reaction at a constant temperature for 1 hour. Add a small amount of water to the reaction solution, stir, filter by suction, and wash the filter residue with water. Dry the solid to obtain the target ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (237 mg, 73.2% yield), LC-MS (m / z) 517.3 (M+1).

[0138] Step 4: Preparation of 2-(3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0139] At room temperature, (ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate) (237 mg, 0.46 mmol) was dissolved in 5 ml of acetic acid, and then sodium acetate (188 mg, 2.3 mmol) was added. The temperature was raised to 100 °C and the mixture was stirred for 4 hours, after which the heating was stopped. The mixture was cooled to room temperature, ice water was added, and a solid precipitated. The solid was filtered, then dissolved in EA, dried and concentrated to obtain a crude red solid. Column chromatography separation (methanol / dichloromethane = 1 / 20) gave the target compound 2-(3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (99 mg, 45.8% yield), LC-MS (m / z) 471.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.93 (d, J = 3.7 Hz, 1H), 7.82 (s, 2H), 6.80 (d, J = 3.6 Hz, 1H), 5.26 (q, J = 8.7 Hz, 1H), 2.61 (p, J = 10.3, 9.9 Hz, 2H), 2.49 - 2.38 (m, 4H), 1.88 (dt, J = 13.3, 6.5 Hz, 2H).

[0140] Example 6 Preparation of 2-(3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0141]

[0142] Step 1: Preparation of 3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline

[0143] Dissolve 2,6-dibromo-4-aminophenol (615 mg, 2.4 mmol) and 4-chloro-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine (364 mg, 2 mmol) in N,N-dimethylformamide (15 ml), and then add cesium carbonate (1.6 g, 5 mmol). After the addition is complete, replace the reaction system with nitrogen for protection, heat and stir to raise the temperature to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and distill under reduced pressure to obtain a residue. Finally, separate by column chromatography (ethyl acetate / petroleum ether = 1 / 2). Obtain the target 3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (114 mg, 13.4% yield), LC-MS (m / z) 413.1 (M+1).

[0144] Step 2: Preparation of ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate

[0145] Dissolve 3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (114 mg, 0.27 mmol) in a solution of hydrochloric acid (3 ml) and water (3 ml), cool down to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (23 mg, 0.33 mmol). Keep the temperature for reaction for 30 minutes to obtain the reaction mother liquor. Dissolve N-cyanoacetylurethane (44 mg, 0.28 mmol) in a solution of pyridine (3 ml) and water (3 ml), cool down to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor into the system. After the addition is complete, the solution turns brown and a solid precipitates. Continue to keep the temperature for reaction for 1 hour. Add a small amount of water to the reaction solution, stir, filter by suction, and wash the filter residue with water. Dry the solid to obtain the target ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (135 mg, 84.4% yield), LC-MS (m / z) 580.3 (M+1).

[0146] Step 3: Preparation of 2-(3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0147] At room temperature, dissolve ethyl (2-cyano-2-(2-(3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (135 mg, 0.23 mmol) in 5 ml of acetic acid, then add sodium acetate (95 mg, 1.15 mmol), heat up to 100 °C and stir the reaction for 4 hours, then stop heating. Cool to room temperature, add ice water, a solid will precipitate out, filter, then add EA to dissolve, dry and concentrate to obtain the crude red solid. Separate by column chromatography (methanol / dichloromethane = 1 / 20) to obtain the target compound 2-(3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (47 mg, 37.8% yield), LC-MS (m / z) 534.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.94 (d, J = 0.7 Hz, 2H), 7.70 (d, J = 3.6 Hz, 1H), 6.76 (d, J = 3.5 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H).

[0148] Example 7 Preparation of 2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0149]

[0150] Step 1: Preparation of 4-chloro-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine

[0151] Dissolve 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (615 mg, 4 mmol) in N,N-dimethylformamide (10 ml), under nitrogen protection, add potassium hydroxide (448 mg, 8 mmol) at room temperature, stir vigorously, then add 1,1-difluoro-2-iodoethane (922 mg, 4.8 mmol), continue to stir the reaction at room temperature for 16 hours. After the reaction is completed, filter, wash the filter cake with ethyl acetate, wash and extract the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, distill under reduced pressure to obtain the residue, and finally separate by column chromatography (ethyl acetate / petroleum ether = 1 / 4). Obtain the target 4-chloro-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine (279 mg, 32.1% yield), LC-MS (m / z) 218.6 (M+1).

[0152] Step 2: Preparation of 3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline

[0153] Dissolve 2,6-dichloro-4-aminophenol (215 mg, 1.2 mmol) and 4-chloro-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine (218 mg, 1 mmol) in N,N-dimethylformamide (10 ml), and then add cesium carbonate (815 mg, 2.5 mmol). After the addition is complete, protect the reaction system by purging with nitrogen, heat with stirring to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase over anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain a residue, which is separated by column chromatography (ethyl acetate / petroleum ether = 1 / 2). The target 3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (259 mg, 72.1% yield) is obtained, LC-MS (m / z) 360.2 (M+1).

[0154] Step 3: Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamic acid ethyl ester)

[0155] Dissolve 3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (259 mg, 0.72 mmol) in a solution of hydrochloric acid (3 ml) and water (3 ml), cool down to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (60 mg, 0.87 mmol). Keep the reaction at 0 - 5 °C for 30 minutes to prepare the reaction mother liquor. Dissolve N-cyanoacetylurethane (118 mg, 0.76 mmol) in a solution of pyridine (3 ml) and water (6 ml), cool down to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor to the system. After the addition is complete, the solution turns orange-red and a solid precipitates. Continue to keep the reaction at the same temperature for 1 hour. Add a small amount of water to the reaction solution, stir, filter by suction, and wash the filter cake with water. Dry the solid to obtain the target ((2-cyano-2-(2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamic acid ethyl ester (279 mg, 73.6% yield), LC-MS (m / z) 527.2 (M+1).

[0156] Step 4: Preparation of 2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0157] At room temperature, dissolve ethyl (2-cyano-2-(2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)carbamate (263 mg, 0.5 mmol) in 10 ml of acetic acid, then add sodium acetate (205 mg, 2.5 mmol). Heat the mixture to 100 °C and stir for 3 hours, then stop heating. Cool to room temperature, add ice water, precipitate the solid, filter it, then dissolve it in ethyl acetate, dry and concentrate to obtain the crude orange solid. Separate by column chromatography (methanol / dichloromethane = 1 / 20) to obtain the light yellow solid 2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (67 mg, 28.0% yield), LC-MS (m / z) 481.2 (M+1). 1 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.83 (s, 2H), 7.68 (d, J = 3.7 Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 6.49 (t, J = 54.6 Hz, 1H), 4.92 - 4.71 (m, 2H).

[0158] Example 8 Preparation of 2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0159]

[0160] Step 1: Preparation of (4-chloro-(7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine)

[0161] Dissolve 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (615 mg, 4 mmol) in N,N-dimethylformamide (10 ml). At room temperature, add cesium carbonate (3.25 g, 10 mmol), then add 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.11 g, 4.8 mmol). Protect with nitrogen displacement, heat to 60 °C and stir for 10 hours. After the reaction is completed, cool the reaction, filter, wash the filter cake with ethyl acetate by stirring, wash and extract the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, distill under reduced pressure to obtain a residue, and finally separate by column chromatography (ethyl acetate / petroleum ether = 1 / 4). Obtain the target 4-chloro-(7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine (413 mg, 43.9% yield), LC-MS (m / z) 236.6 (M+1).

[0162] Step 2: Preparation of (4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline)

[0163] Dissolve 2,6-dichloro-4-aminophenol (356 mg, 2.0 mmol) and 4-chloro-(7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 1.7 mmol) in N,N-dimethylformamide (10 ml), and then add cesium carbonate (1.37 g, 4.2 mmol). After adding the materials, protect the reaction system with nitrogen displacement, heat and stir to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system and stir and filter, add saturated brine to the filtrate, extract, dry the organic phase over anhydrous sodium sulfate, filter, distill under reduced pressure to obtain a residue, and perform column chromatography separation (ethyl acetate / petroleum ether = 1 / 2). Obtain the target 4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (238 mg, 37.1% yield), LC-MS (m / z) 378.2 (M+1).

[0164] Step 3: Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)ethylcarbamate)

[0165] 4-((7-(2,2,2-Trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)aniline (238 mg, 0.63 mmol) was dissolved in a solution of hydrochloric acid (3 ml) and water (3 ml). The temperature was cooled down to 0 - 5 °C, and then an aqueous solution of sodium nitrite (52 mg, 0.76 mmol) was added dropwise. The reaction was maintained at 0 - 5 °C for 30 minutes to obtain the reaction mother liquor. N-Cyanoacetylurethane (103 mg, 0.66 mmol) was dissolved in a solution of pyridine (3 ml) and water (6 ml). The temperature was cooled down to 0 - 5 °C, and then the above-prepared diazonium salt reaction mother liquor was added dropwise to the system. After the addition was complete, the solution turned orange-red and a solid precipitated. The reaction was continued at the same temperature for 1 hour. A small amount of water was added to the reaction solution, stirred, filtered, and the filter cake was washed with water. The solid was dried to obtain the target (2-cyano-2-(2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate (277 mg, 80.8% yield), LC-MS (m / z) 545.3 (M+1).

[0166] Step 4: Preparation of 2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0167] At room temperature, (2-cyano-2-(2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate (277 mg, 0.5 mmol) was dissolved in 10 ml of acetic acid, and then sodium acetate (205 mg, 2.5 mmol) was added. The temperature was raised to 100 °C and stirred for 3 hours, then the heating was stopped. After cooling to room temperature, ice water was added, and a solid precipitated. It was filtered, then dissolved in ethyl acetate, dried and concentrated to obtain a crude orange solid. Column chromatography separation (methanol / dichloromethane = 1 / 20) gave a light yellow solid 2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (85 mg, 34.1% yield), LC-MS (m / z) 499.2 (M+1). 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.84 (s, 2H), 7.73 (d, J = 3.7 Hz, 1H), 6.93 (d, J = 3.7 Hz, 1H), 5.27 (q, J = 9.2 Hz, 2H).

[0168] Example 9 Preparation of 2-(3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0169]

[0170] Step 1: Preparation of (3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)aniline)

[0171] Dissolve 2,6-dichloro-4-aminophenol (427 mg, 2.4 mmol) and 6-chloro-9-methylpurine (337 mg, 2 mmol) in N,N-dimethylformamide (15 ml), and then add cesium carbonate (1.63 g, 5 mmol). After the addition is complete, replace the reaction system with nitrogen for protection, heat and stir to raise the temperature to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and distill under reduced pressure to obtain a residue. Finally, separate by column chromatography (ethyl acetate / petroleum ether = 1 / 1). The target 3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)aniline (388 mg, 62.6% yield) is obtained, LC-MS (m / z) 311.1 (M+1).

[0172] Step 2: Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate)

[0173] Dissolve 3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)aniline (388 mg, 1.25 mmol) in a solution of hydrochloric acid (4 ml) and water (5 ml), cool to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (104 mg, 1.5 mmol). Keep the temperature for 30 minutes to prepare the reaction mother liquor. Dissolve N-cyanoacetylurethane (205 mg, 1.3 mmol) in a solution of pyridine (4 ml) and water (8 ml), cool to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor to the system. After the addition is complete, the solution turns red and a solid precipitates. Keep the temperature for 1 hour. Add a small amount of water to the reaction solution, stir, filter, and wash the filter residue with water. Dry the solid to obtain the target ((2-cyano-2-(2-(3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate (414 mg, 69.4% yield), LC-MS (m / z) 478.3 (M+1).

[0174] Step 3: Preparation of 2-(3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0175] At room temperature, ethyl (2-cyano-2-(2-(3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (414 mg, 0.87 mmol) was dissolved in 5 ml of acetic acid, and then sodium acetate (360 mg, 4.4 mmol) was added. The temperature was raised to 100 °C and stirred for 3 hours, and then the heating was stopped. After cooling to room temperature, ice water was added, and a solid was precipitated. The solid was filtered, then dissolved in tetrahydrofuran, dried and concentrated to obtain a crude red solid. Column chromatography separation (methanol / dichloromethane = 1 / 15) gave an orange solid 2-(3,5-dichloro-4-((9-methyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (185 mg, 49.3% yield), LC-MS (m / z) 432.2 (M+1). 1 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 21.8 Hz, 1H), 7.84 (s, 1H), 3.88 (s, 2H).

[0176] Example 10 Preparation of 2-(3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0177]

[0178] Step 1: Preparation of (3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)aniline)

[0179] Dissolve 2,6-dichloro-4-aminophenol (427 mg, 2.4 mmol) and 6-chloro-9-isopropylpurine (393 mg, 2 mmol) in N,N-dimethylformamide (15 ml), and then add cesium carbonate (1.63 g, 5 mmol). After the addition is complete, replace the reaction system with nitrogen for protection, heat and stir to raise the temperature to 120 °C, react for 1 hour, stop heating, add ethyl acetate to the reaction system, stir and filter, add saturated brine to the filtrate, extract, dry the organic phase, filter, and distill under reduced pressure to obtain a residue. Finally, separate by column chromatography (ethyl acetate / petroleum ether = 1 / 1). Obtain the target 3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)aniline (431 mg, 63.8% yield), LC-MS (m / z) 339.2 (M+1).

[0180] Step 2: Prepare ((2-cyano-2-(2-(3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate)

[0181] Dissolve 3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)aniline (431 mg, 1.27 mmol) in a solution of hydrochloric acid (4 ml) and water (5 ml), cool down to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (104 mg, 1.5 mmol). Keep the temperature for reaction for 30 minutes to obtain the reaction mother liquor. Dissolve N-cyanoacetylurethane (205 mg, 1.3 mmol) in a solution of pyridine (4 ml) and water (8 ml), cool down to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor into the system. After the addition is complete, the solution turns red and a solid precipitates. Continue to keep the temperature for reaction for 1 hour. Add a small amount of water to the reaction solution, stir, filter by suction, and wash the filter residue with water. Dry the solid to obtain the target ((2-cyano-2-(2-(3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate (472 mg, 73.6% yield), LC-MS (m / z) 506.3 (M+1).

[0182] Step 3: Prepare 2-(3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0183] At room temperature, (ethyl (2-cyano-2-(2-(3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate) (472 mg, 0.93 mmol) was dissolved in 10 ml of acetic acid, and then sodium acetate (385 mg, 4.7 mmol) was added. The temperature was raised to 100 °C and the mixture was stirred for 5 hours, after which heating was stopped. It was cooled to room temperature, ice water was added, and a solid precipitated. It was filtered, then dissolved in tetrahydrofuran, dried and concentrated to obtain a crude red solid. Column chromatography separation (methanol / dichloromethane = 1 / 15) gave the orange solid 2-(3,5-dichloro-4-((9-isopropyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (204 mg, 47.8% yield), LC-MS (m / z) 460.3 (M+1). 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.50 (s, 1H), 7.84 (d, J = 0.8 Hz, 2H), 5.03 - 4.80 (m, 1H), 1.60 (d, J = 6.8 Hz, 7H).

[0184] Example 11 Preparation of 2-(3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0185]

[0186] Step 1: Preparation of (3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)aniline)

[0187] 2,6-Dichloro-4-aminophenol (321 mg, 1.8 mmol) and 6-chloro-9-cyclopropylpurine (292 mg, 1.5 mmol) were dissolved in N,N-dimethylformamide (10 ml), and then cesium carbonate (1.24 g, 3.8 mmol) was added. After the addition was complete, the reaction system was protected by purging with nitrogen, heated and stirred to 120 °C, and reacted for 1 hour. Heating was stopped, ethyl acetate was added to the reaction system and stirred and filtered. Saturated brine was added to the filtrate for extraction, the organic phase was dried, filtered, and the residue was obtained by distillation under reduced pressure. Finally, column chromatography separation (ethyl acetate / petroleum ether = 1 / 2) was carried out. The target 3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)aniline (342 mg, 67.8% yield) was obtained, LC-MS (m / z) 337.2 (M+1).

[0188] Step 2: Preparation of ((2-cyano-2-(2-(3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)ethylcarbamate)

[0189] Dissolve 3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)aniline (340 mg, 1 mmol) in a solution of hydrochloric acid (4 ml) and water (5 ml), cool down to 0 - 5 °C, and then dropwise add an aqueous solution of sodium nitrite (83 mg, 1.2 mmol). Keep the reaction at a constant temperature for 30 minutes to obtain the reaction mother liquor. Dissolve N-cyanoacetylurethane (164 mg, 1.05 mmol) in a solution of pyridine (4 ml) and water (8 ml), cool down to 0 - 5 °C, and then dropwise add the above-prepared diazonium salt reaction mother liquor into the system. After the addition is complete, the solution turns red and a solid precipitates. Continue to keep the reaction at a constant temperature for 1 hour. Add a small amount of water to the reaction solution, stir, filter by suction, and wash the filter residue with water. Dry the solid to obtain the target ((2-cyano-2-(2-(3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)ethylcarbamate) (387 mg, 76.9% yield), LC-MS (m / z) 504.3 (M + 1).

[0190] Step 3: Preparation of 2-(3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0191] At room temperature, dissolve ((2-cyano-2-(2-(3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)phenyl)hydrazono)acetyl)ethylcarbamate) (387 mg, 0.77 mmol) in 10 ml of acetic acid, then add sodium acetate (316 mg, 3.85 mmol), heat up to 100 °C and stir the reaction for 3 hours, then stop heating. Cool to room temperature, add ice water, and a solid precipitates. Filter, then dissolve in tetrahydrofuran, dry and concentrate to obtain a crude red solid. Separate by column chromatography (methanol / dichloromethane = 1 / 15) to obtain the orange solid 2-(3,5-dichloro-4-((9-cyclopropyl-9H-purin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (138 mg, 39.2% yield), LC-MS (m / z) 458.3 (M + 1). 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.51 (s, 1H), 7.83 (s, 2H), 5.76 (s, 1H), 1.16 (dd, J = 30.9, 5.4 Hz, 4H).

[0192] Comparative example:

[0193] Comparative example 1: 2-(3,5-dichloro-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile).

[0194] For its structure and preparation method, refer to Example 1 of CN112300133A.

[0195]

[0196] Comparative example 2:

[0197] 2-(3,5-dichloro-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0198] For its structure and preparation method, refer to Example 4 of CN112300133A.

[0199]

[0200] Comparative example 3:

[0201] 2-(3,5-dibromo-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile

[0202] For its structure and preparation method, refer to Example 6 of CN112300133A.

[0203]

[0204] Transcription activation experiment of human thyroid hormone receptors α1 (TRα1) and β1 (TRβ1) in Example 12

[0205] The pcDNA3.1 vectors of TRα1 or TRβ1 cloned from human liver cells and the firefly luciferase vector pTA-TRE-Luc with a thyroid hormone response sequence (manufactured by Promega) were transfected into CV-1 cells cultured in Dulbecco’s modified Eagle medium (DMEM) using X-tremeGENE HP DNA Transfection Reagent (manufactured by Roche). Sixteen hours after transfection, the compound diluted with dimethyl sulfoxide solution was added, and the luciferase activity was measured 24 hours later.

[0206] Using 3,3’,5-triiodo-L-thyronine (T3) as a positive control, the transcriptional activation effects of the compound on TRα1 and TRβ1 were shown by the respective EC 50 values relative to the maximum luciferase activity value of T3 being 100%, and the maximum luciferase activity value. The EC 50 and selectivity, nearly 50% active dose, as well as the maximum agonist activity and its concentration of the compounds of the present invention are shown in Tables 1 - 3 below. Among them, the selectivity (α / β) is TRα EC 50 / TRβ1 EC 50 .

[0207] Examples <![CDATA[TRβ1EC 50 (μM)]]> Selectivity (α / β) Examples <![CDATA[TRβ1EC 50 (μM)]]> Selectivity (α / β) Example 1 0.8862 ＞11.28 Example 2 0.4615 ＞21.67 Example 3 0.2442 ＞40.95 Example 4 0.1373 ＞72.83 Example 5 0.08098 ＞123.49 Example 6 ＜0.3 ＞33.33 Example 7 0.763 58.23 Example 8 0.959 21.88 Comparative example 1 2.717 3.31 Comparative example 2 3.393 / Comparative example 3 3.602 /

[0208] The results of the transcriptional activation experiment according to Table 1 show that the compounds of the examples of the present invention can achieve agonist activity on thyroid hormone receptor β; and compared with Comparative Examples 1, 2, and 3, the agonist activity of the compounds of each example of the present invention on TRβ is unexpectedly significantly improved; at the same time, each example of the present invention also shows very high selectivity for TRβ1, showing an unexpected effect compared with Comparative Example 1.

[0209] Table 2 Nearly 50% active dose of the compounds of the present invention

[0210]

[0211] The nearly 50% active dose refers to the concentration of the compound when the activities of respectively activating the α subtype and the β subtype reach 50% of that when T3 is used as 100%. This data can show the agonist activities of the compound on TRα and TRβ.

[0212] According to the above data in Table 2, the TRα agonist activity of Comparative Example 1 reached 50% at 10 μm, while in Examples 1-3, values near 50% of agonist activity (measured values) were not measured even at 30 μm. At a concentration of 1 μm, the agonist activity of Example 1 against β was stronger than that of Comparative Example 1, and Examples 2 and 3 could reach nearly 50% at 0.3 μm. This effect is difficult to predict.

[0213] Examples max%(α) Cmax(α) max%(β) Cmax(β) Comparative example 1 49.36 10 57.35 3 Example 1 33.91 10 59.25 1 Example 2 39.29 10 70.80 3 Example 3 39.58 3 73.84 1

[0214] max% is the maximum agonist activity of the compound (taking 100% when stimulated by T3), and Cmax refers to the compound concentration corresponding to max%.

[0215] According to the above data in Table 3, the max% of Comparative Example 1 against the α subtype was significantly higher than that of Examples 1-3, while the max% against the β subtype was significantly lower than that of Examples 1-3. This shows that compared with Comparative Example 1, the compounds of the present invention have stronger agonist activity against the β subtype and weaker agonist activity against the α subtype, demonstrating better selectivity while having better β agonist activity. This effect is difficult to predict.

[0216] Industrial Applicability

[0217] The heterocyclic compounds of the present invention have good thyroid hormone β receptor agonist activity and can be used as drugs for treating or preventing diseases related to this effect.

[0218] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A heterocyclic compound, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The heterocyclic compound is a specific compound selected from the following: 2-(3,5-dibromo-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile; 2-(3,5-dichloro-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile; 2-(3,5-dichloro-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile; 2-(3,5-dibromo-4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile; 2-(3,5-dichloro-4-((7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile; 2-(3,5-dibromo-4-((7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile; 2-(3,5-dichloro-4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile; 2-(3,5-dichloro-4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile.

2. A pharmaceutical composition comprising a therapeutically effective amount of the heterocyclic compound as described in claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, and optionally a pharmaceutically acceptable pharmaceutical carrier and / or excipient and / or diluent.

3. Use of the heterocyclic compound as described in claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof or the pharmaceutical composition as described in claim 2 in the preparation of a thyroid hormone β1 receptor agonist.

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